Design of novel leads: ligand based computational modeling studies on non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1

摘要

Researchers are on the constant lookout for new antiviral agents for the treatment of AIDS. In the present work, ligand based modeling studies are performed on analogues of substituted phenyl-thio-thymines, which act as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and novel leads are extracted. Using alignment-dependent descriptors, based on group center overlap (S_(ALL), HD_(ALL), HA_(ALL) and R_(ALL)), an alignment-independent descriptor (Slog P), a topological descriptor (Balaban index (J)) and a 3D descriptor dipole moment (μ) and shape based descriptors (Kappa 2 index (~2k)), a correlation is derived with inhibitory activity. Linear and non-linear techniques have been used to achieve the goal. Support Vector Machine (SVM, R = 0.929, R~2 = 0.863) and Back Propagation Neural Network (BPNN, R = 0.928, R~2 = 0.861) methods yielded near similar results and outperformed Multiple Linear Regression (MLR, R = 0.915, R~2 = 0.837). The predictive ability of the models are cross-validated using a test dataset (SVM: R = 0.846, R~2 = 0.716, BPNN: R = 0.841, R~2 = 0.707 and MLR: R = 0.833, R~2 = 0.694). It is concluded that the hydrophobicity (Slog P) and the polarity (μ) of a ligand and the presence of hydrogen donor (HD_(ALL)) moieties are the deciding factors in improving antiviral activity and pharmaco-therapeutic properties. Based on the above findings, a virtual dataset is created to extract probable leads with reasonable antiviral activity as well as better pharmacophoric properties.